Chymase is stored as an ingredient in granules of mast cells (MC), which are one of the inflammatory cells closely related to inflammation, and is widely present mainly in the tissue such as skin, heart, vascular walls, intestines etc. (see Non-Patent Document 1). Human chymase is known as an enzyme for specifically producing angiotensin II (i.e., Ang II) from angiotensin I (i.e., Ang I) independently from angiotensin converting enzyme. There is a report that, in human cardiac tissue, 80% of the production of angiotensin II is derived from by chymase (see Non-Patent Document 2). Ang II is known to be closely related to regulation of the blood pressure, diuretic regulation, and hypertrophy and remodeling of the cardiovascular system, that is, the migration and proliferation of smooth muscle cells etc. and the growth of the extracellular matrix in the cardiovascular system tissue. From these findings, it is suggested that chymase is closely related to cardiovascular lesions through production of Ang II. In addition to production of Ang II, it is reported that chymase has the following actions based on its protease activity:
1) degradation of the extracellular matrix (see Non-Patent Document 3) and production of collagen (see Non-Patent Document 4);
2) activation of matrix metalloprotease (see Non-Patent Document 5 and Non-Patent Document 6).
3) processing and activation of cytokine, for example, release of latent TGFβ1 from extracellular matrix (see Non-Patent Document 7), activation of latent TGFβ1 to active TGFβ1 (see Non-Patent Document 8) and activation of IL-1β (see Non-Patent Document 9);4) activation of stem cell factor (SCF) which induces differentiation and proliferation of MCs (see Non-Patent Document 10);5) degradation of apolipoprotein B in LDL (see Non-Patent Document 11) and degradation of apolipoprotein A in HDL (see Non-Patent Document 12); and6) conversion of big endothelin to a bioactive peptide comprised of 31 amino acid residues (ET(1-31)) (see Non-Patent Document 14).
Further, it is reported that chymase stimulates rat peritoneal mast cells to induce degranulation (see Non-Patent Document 15) and that administration of human chymase intraperitoneally to mice or subcutaneously to guinea pigs induces infiltration of eosinophil and other leukocytes (see Non-Patent Document 16), and causes continuous increase of vascular permeability not through the action of histamine (see Non-Patent Document 17). These various reports relating to the action of chymase suggest that chymase plays an important role in the processes of tissue inflammation, repair, and healing, and in allergic conditions. It is believed that in these processes, the excessive reaction of chymase is involved in various diseases.
From the above-mentioned findings, a chymase inhibitor can be expected to be useful as a pharmaceutical for the prevention or treatment of, for example, bronchial asthma, chronic obstructive pulmonary disease, urticaria, atopic dermatitis, allergic conjunctivitis, rhinitis, rheumatoid arthritis, food allergies, colitis, allergic enteritis, mastocytosis, scleroderma, heart failure, cardiac hypertrophy, hypertension, arrhythmia, atherosclerosis, abdominal aortic aneurysm, myocardial infarction, restenosis after PTCA, restenosis after bypass graft surgery, ischemic peripheral circulatory disorders, hyperaldosteronism, diabetes, diabetic retinopathy, diabetic nephropathy, nephritis, glomerulosclerosis, renal insufficiency, solid tumor, fibrosis, postoperative adhesion, cicatrix, glaucoma, and ocular hypertension.
On the other hand, small molecule chymase inhibitors are already shown in books (see Non-Patent Document 18) or review articles (see Non-Patent Documents 19, 20, and 21). The efficacy of several inhibitors among these in animal disease models has been reported.
Heart failure: see Non-Patent Document 22,
Myocardial infarction: see Non-Patent Document 23 and see Non-Patent Document 24,
Arrhythemia; see Non-Patent Document 25,
Abdominal aortic aneurysm: see Non-Patent Document 26 and Non-Patent Document 27,
Vascular restenosis: see Non-Patent Document 28,
Lipid accumulation in the aorta: see Non-Patent Document 29,
Diabetes: see Non-Patent Document 30,
Nephritis: see Non-Patent Document 31,
Fibrosis: see Non-Patent Document 32 and Non-Patent Document 33,
Post-operative adhesion: see Non-Patent Document 34,
Glaucoma: see Patent Document 1,
Hypereosinophilia: see Patent Document 2,
Atopic dermatitis: see Non-Patent Document 35,
Pruritus: see Non-Patent Document 36,
Asthma: see Non-Patent Document 37,
Enteritis: see Non-Patent Document 38.
Further, recently, in addition to the chymase inhibitors described in the above books and reviews, imidazoledinedione derivatives (see Patent Document 3), phosphonic acid and phosphinic acid derivatives (see Patent Document 4, Patent Document 5, and Patent Document 6), benzothiophene sulfonamide derivatives (see Patent Document 7 and Patent Document 8), imidazole, thiazolimine, and oxazolimine derivatives (see Patent Document 9 and Patent Document 10), triazolidine derivatives (see Patent Document 11), pyridone derivatives (see Patent Document 12), indole derivatives (see Patent Document 13 and Patent Document 14), ring-fused pyrrole derivatives (see Patent Document 15), imidazopyridine derivatives (see Patent Document 16), benzimidazolone derivatives (see Patent Document 17), quinazolinedinone derivatives (see Patent Document 18), phthalazinone derivatives (see Patent Document 20), azabenzoimidazolone derivatives (see Patent Document 21), and azaquinazolinedinone derivatives (see Patent Document 22) are disclosed as novel chymase inhibitors. However, there are no examples of practical application of the above chymase inhibitors as pharmaceuticals.
Further, 1,4-diazepan-2,5-dione derivatives are disclosed in documents as chymase inhibitors similar in structure to the present invention (see Patent Document 19), but these compounds and the compounds of the present invention are different in structure.